Submissions for variant NM_000090.4(COL3A1):c.3593G>A (p.Gly1198Asp)

gnomAD frequency: 0.00001  dbSNP: rs756858564

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812113	SCV000952417	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-08-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1198 of the COL3A1 protein (p.Gly1198Asp). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with thoracic aortic aneurysm/dissection (PMID: 30675029). ClinVar contains an entry for this variant (Variation ID: 655850). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL3A1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001186025	SCV001352353	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 1198 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with COL3A1-related disorders in the literature. This variant has been identified in 5/251366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001593002	SCV001824505	uncertain significance	not provided	2024-05-15	criteria provided, single submitter	clinical testing	Has been reported in a patient with a personal and family history of TAAD who also harbored a COL2A1 variant (PMID: 30675029); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); This variant is associated with the following publications: (PMID: 30675029)
Ambry Genetics	RCV001186025	SCV002619434	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-07-30	criteria provided, single submitter	clinical testing	The p.G1198D variant (also known as c.3593G>A), located in coding exon 48 of the COL3A1 gene, results from a G to A substitution at nucleotide position 3593. The glycine at codon 1198 is replaced by aspartic acid, an amino acid with similar properties, and is located in the C-terminal region. The majority (approximately two-thirds) of COL3A1 mutations identified to date have involved the substitution of another amino acid for glycine within the triple-helical domain (Pepin MG et al. Genet Med. 2014;16(12):881-8; Frank M et al. Eur J Hum Genet. 2015;23(12):1657-64). This amino acid position is highly conserved in available vertebrate species; however, aspartic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000812113	SCV004824903	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 1198 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/251366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.